This R21 investigates brain responses to methamphetamine (METH) in a sample of 24-30 healthy volunteers aged 18-35. Background: Methamphetamine (METH) produces behavioral and subjective activation via its acute effects on monoamines, particularly dopamine and serotonin. Unlike other psychostimulants, such as d- amphetamine, METH produces a large, sustained serotonin increase after consumption. Use and misuse of METH is an increasing public health problem. In the last decade, METH usage has surged in a west to east pattern, with large numbers of young adults reporting recreational use of street-, black-market- and prescribed- methamphetamines. Despite these trends, there has been very little actual study of the impact of METH on brain responses after drug consumption that would assist in understanding specific vulnerability factors for METH use and misuse. The present study begins to fill this gap, collecting preliminary data on fMRI brain responses to METH in a sample of healthy volunteers. Overall experimental approach / design: The project utilizes functional magnetic resonance imaging (fMRI) to investigate the neural correlates of METH exposure, using a within-subjects, counterbalanced, placebo-controlled METH administration procedure (20 mg oral) in N=24-30 healthy prescreened volunteers. The proposal includes an amphetamine condition (20 mg oral), which serves as a positive control to identify unique responses to METH compared to AMP within-subjects. We expect elevated METH effects on brain responses to reward and punishment due to serotonergic impact of METH, and the modulation of these effects by a personality trait known to relate to between-subject differences in the sensitivity of ascending serotonin systems (i.e., Trait impulsivity;Depue &White, 2009). The project has impact and significance for public health because it 1.) documents with fMRI where and how brain systems of potentially vulnerable individuals are most sensitive to METH;2.) identifies the types of brain processes most altered in these individuals, and 3.) provides evidence that can be used to guide targeted prevention efforts to reduce METH use and misuse in young adults. PUBLIC HEALTH RELEVANCE: The study is relevant to public health as it informs neural risk factors for the vulnerability to methamphetamine effects in normal populations, which may assist in better understanding and preventing the significant public health problem of methamphetamine use and dependence in healthy and addicted populations.